EP1341786B9 - Substituierte amino-furan-2-yl-essigsaure- und amino-thien-2-yl-essigsaure-derivate und ihre verwendung zur behandlung von migraine bzw. schmerz - Google Patents

Substituierte amino-furan-2-yl-essigsaure- und amino-thien-2-yl-essigsaure-derivate und ihre verwendung zur behandlung von migraine bzw. schmerz Download PDF

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Publication number
EP1341786B9
EP1341786B9 EP01998547A EP01998547A EP1341786B9 EP 1341786 B9 EP1341786 B9 EP 1341786B9 EP 01998547 A EP01998547 A EP 01998547A EP 01998547 A EP01998547 A EP 01998547A EP 1341786 B9 EP1341786 B9 EP 1341786B9
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Prior art keywords
methyl
furan
phenylamino
acetic acid
chloro
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EP01998547A
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German (de)
English (en)
French (fr)
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EP1341786A1 (de
EP1341786B1 (de
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Corinna Sundermann
Werner Englberger
Michael Przewosny
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to CY20091100279T priority patent/CY1108871T1/el
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to substituted amino-furan-2-yl-acetic acid and substituted amino-thien-2-yl-acetic acid derivatives, processes for their preparation, medicines containing them, use of these compounds for the preparation of medicaments for the treatment of i.a. Pain or migraine and pharmaceutical compositions containing them.
  • Opioids exert their analgesic effect by binding to cell-membrane receptors belonging to the family of so-called G protein-coupled receptors.
  • G protein-coupled receptors there are other receptors as well as ion channels that are essential to the system of pain development and pain transmission,
  • NMDA ion channel N-methyl-D-aspartate ion channel
  • NMDA ion channel through which a significant part of the communication of synapses takes place and by the calcium ion exchange between a neuronal cell and its environment is controlled (see, for example PD Leeson, LL Iversen, J. Med. Chem. 37 (1994) 4053-4067 ).
  • the compounds of general structure (I) according to the invention are either amino-furan-2-yl-acetic acid derivatives of general structure (IA) or amino-thien-2-yl-acetic acid derivatives of general structure (IB):
  • C 1-6 -alkyl in the context of this invention comprises unsubstituted, acyclic saturated hydrocarbon radicals which may be branched or straight-chain, having 1 to 6 (ie, 1, 2, 3, 4, 5 or 6) carbon atoms ie C 1-6 alkanyle.
  • alkyl is selected from the group consisting of methyl, ethyl, n -propyl, 2-propyl, n -butyl, iso -butyl, sec -butyl, tert -butyl, n -pentyl, isopentyl, neo -pentyl, n -Hexyl and 2-hexyl.
  • Pharmaceutically acceptable salts in the context of this invention are those salts of the compounds of the invention according to the general structure (I), which are physiologically compatible in pharmaceutical use - in particular for use in mammals and / or humans.
  • Such pharmaceutically acceptable salts may be formed, for example, with inorganic or organic acids or, in the case where the compounds of the invention are acids, especially carboxylic acids, are formed with bases.
  • the salts formed are, inter alia, hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates or sodium salts. Also preferred are solvates and in particular the hydrates of the compounds of the invention, which can be obtained, for example, by crystallization from aqueous solution.
  • the product obtained is the corresponding amino-furan-2-yl-acetic acid derivative of the general structure (IA), whereas the thiophene derivative (IV-B) is used as a product of the inventive 3-component reaction, the corresponding amino-thien-2-yl-acetic acid derivative of the general structure (IB).
  • reaction component glyoxylic acid (III) is preferably used in the form of its hydrate.
  • the process according to the invention can be carried out in the presence of small amounts of an inorganic or especially organic acid, for example trifluoroacetic acid, preferably in catalytic amounts of about 1-10 mol% (based on the starting material (II)).
  • an inorganic or especially organic acid for example trifluoroacetic acid
  • the reaction can also without addition of an acid or another reagent by mere mixing of the starting compounds (II), (III) and (IV-A) or (IV- B), preferably in an organic solvent, for example acetonitrile, and then stirring at temperatures between 0 ° C and 100 ° C - possibly also as a one-pot process - be performed.
  • furan derivative (IV-A) or thiophene derivative (IV-B) in excess of, for example, 1.5 to 4.5 mol equivalents, in particular 2.5 to 3.5 mol equivalents (based on starting material (II)) to use.
  • reaction time 8 h to about 18 h, in particular 14 h, appropriate.
  • the 3-component reaction according to the invention can also be carried out under the action of microwave radiation, whereby the reaction time for a substantially complete reaction to a few minutes, e.g. to 0.5 min to 5 min, shortened.
  • the reaction temperature is preferably at 15 ° C to 60 ° C, in particular about 50 ° C, selected.
  • microwave irradiation for example, a laboratory microwave from the company MLS GmbH (D-88299 Leutkirch, Auenweg 37, Germany), model MLS ETHOS 600 with a power of about 800 W.
  • the implementation takes place recordable in a pressure-stable Teflon vessel.
  • the process according to the invention can also be carried out in semi- or fully automated form as a parallel synthesis of a group of compounds of the general structure (I) according to the invention.
  • This technique and by the reaction of the compounds (II), (III) and (IV-A) or (IV-B) can also be a substance library in the form of an "array of compounds" build.
  • This substance library contains the library members which are the reaction products of the reaction of the compounds (II), (III) and (IV-A) or (IV-B) as single pure compounds.
  • a medical screening in one or more in vitro screening methods can be carried out in an automated form.
  • the amines of the general structure (II) used in the process according to the invention, the glyoxylic acid derivatives of the general structure (III), the furan derivatives of the general structure (IV-A) and the thiophene derivatives of the general structure (IV-B) commercially available (from Acros, Geel, Avocado, Port of Heysham, Aldrich, Deisenhofen, Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCI, Japan) or can be prepared by methods well known in the art.
  • the compounds of the general structure (I) according to the invention can be isolated both in substance and as a salt.
  • the compound of the general structure (I) according to the invention is usually obtained after the reaction according to the above-described inventive method and subsequent conventional work-up.
  • the compound of general structure (I) thus obtained or obtained in situ without isolation can then be, for example, by reaction with an inorganic or organic acid, preferably hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic and acetic acid , Oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic or aspartic acid are converted into the corresponding salt.
  • salt formation can be brought about by addition of a physiologically compatible base, for example NaHCO 3 or sodium carbonate; in particular, the formation of the sodium salt is preferred for the carboxylic acids.
  • a physiologically compatible base for example NaHCO 3 or sodium carbonate
  • the salts formed include hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates.
  • hydrochloride formation may also be accomplished by the reaction of the base dissolved in a suitable organic solvent such as butan-2-one (methyl ethyl ketone) with trimethylsilyl chloride (TMSCI), advantageously in the presence of water.
  • a suitable organic solvent such as butan-2-one (methyl ethyl ketone)
  • TMSCI trimethylsilyl chloride
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of general structure (I) as defined above, or one of its pharmaceutical salts, in particular the hydrochloride salt.
  • the medicament according to the invention preferably contains at least one of the above-exemplified compounds in substance or as a pharmaceutically acceptable salt and optionally other active substances and adjuvants.
  • compositions according to the invention are carried out by means well known in the art of pharmaceutical formulation, devices, methods and methods as described, for example, in U.S. Pat. Remington's Pharmaceutical Sciences, ed. AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985 ), in particular in Part 8, Chapters 76 to 93.
  • Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and / or cellulose acetate.
  • reaction mixture was stirred at 40 ° C in a stirring block for 600 minutes. Thereafter, the reaction solution was filtered off. The tube was rinsed twice with 1.5 ml of 7.5% NaHCO 3 solution.
  • the rack with the samples was manually placed on a processing plant.
  • the reaction mixture was added to a vortexer with 2 ml of ethyl acetate and shaken.
  • To form the phase boundary was briefly centrifuged in the centrifuge.
  • the phase boundary was optically detected and the organic phase was pipetted off.
  • the aqueous phase was added again with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase was pipetted off.
  • the combined organic phases are dried over 2.4 g of MgSO 4 (granulated).
  • the solvent was removed in a vacuum centrifuge.
  • Each sample was analyzed by ESI-MS and / or NMR.
  • the reactions under microwave irradiation were carried out in a laboratory microwave of the make MLS ETHOS 600 from MLS-GmbH (D-88299 Leutkirch, Auenweg 37, Germany).
  • ⁇ 1.15 ppm (t, 3H, CH 3 ); 2.20 ppm (s, 3H, 2-CH 3 thiophene); 4.10 ppm (q, 2H, OCH 2 ); 5.50 ppm (d, 1 H, ⁇ -CH); 6.65 ppm (s, 2H, aryl-2-H and aryl-6H); 6.80 ppm (d, 1H, thiophene-H); 7.28 ppm (d, 1H, thiophene-H).
  • ⁇ 1.22 ppm (s, 9H, tert -Bu); 5.24 ppm (d, 1 H, ⁇ -CH); 5.99 ppm (d, 1H, furan H); 6.26 ppm (d, 1H, furan H); 6.54 ppm (s, 1H, aryl-4-CH); 6.73 ppm (s, 2H, aryl-2H and aryl-6H); 8.27 ppm (d, 1 H, ⁇ -NH); 13.80 ppm (s (broad), 1H, CO 2 H).
  • ⁇ 1.25 ppm (s, 9H, tert -butyl); 5.30 ppm (m, 1H, ⁇ -CH); 6.00 ppm (d, 1H, furyl-H); 6.30 ppm (d, 1H, furyl-H); 6.65 ppm (m, 1H, ⁇ -NH); 6.70 ppm (s, 1H, aryl-H); 6.75 ppm (s, 2H, aryl-H).
  • ⁇ 2.02 ppm (s, 3H, SCH 3 ); 3.69 ppm (s, 2H, CH 2 S); 5.30 ppm (d, 1H, ⁇ -CH); 6.22 ppm (s, 1H, furan H); 6.37 ppm (s, 1H, furan H); 6.63 ppm (s, 1H, aryl-4-H); 6.73 ppm (s, 2H, aryl-2-H and aryl-4H); 6.79 ppm (d, 1 H, ⁇ -NH); 13.17 ppm (s (broad), 1H, CO 2 H).
  • ⁇ 2.08 ppm (s, 3H, SCH 3 ); 2.50 ppm (2, 2H, CH 2 S); 3.70 ppm (s, 2H, ⁇ -NH 2 + ); 5.37 ppm (m, 1H, ⁇ -CH); 6.25 ppm (d, 1H, furan H); 6.40 ppm (d, 1H, furan H); 6.80 ppm (s, 1H, aryl-4H); 6.78 pm (s, 2H, aryl-2-H and aryl-6-H) .
  • ⁇ 3.68 ppm (s, 2H, CH 2 S); 3.73 (s, 2H, CH 2 S); 5.33 (d, 1H, ⁇ -CH); 5.72 ppm (m, 1H, furan H); 6.26 ppm (d, 1H, furan H); 6.27 ppm (d, 1H, furan H); 6.36 ppm (d, 1H, furan H); 6.39 ppm (d, 1H, furan H); 6.64 ppm (s, 1H, aryl-4-H); 6.74 ppm (s, 2H, aryl-2-H and aryl-6-H); 7.55 ppm (d, 1 H, ⁇ -NH); 13.23 ppm (s (broad), 1 H, CO 2 H).
  • ⁇ 2.35 ppm (s, 3H, COCH 3 ); 4.13 ppm (s, 2H, CH 2 S); 5.28 ppm (d, 1 H, ⁇ -CH); 6.24 ppm (s, 1H, furan H); 6.35 (d, 1H, furan-H); 6.63 ppm (s, 1H, aryl-4-H); 6.71 ppm (s, 2H, aryl-2-H and aryl-6-H); 8.29 ppm (d, 1 H, ⁇ -NH); 13.13 ppm (s (broad), 1 H, CO 2 H).
  • ⁇ 2.05 ppm (s, 3H, COCH 3 ); 5.00 ppm (s, 2H, CH 2 O); 5.20 ppm (m, 1H, ⁇ -CH); 6.40-6.50 ppm (m, 2H, furyl-H); 6.60 ppm (s, 1H, aryl-H); 6.65 ppm (s, 2H, aryl-H); 6.80 ppm (d, 1 H, ⁇ -NH).
  • ⁇ 5.25 ppm (m, 1H, ⁇ -CH); 6.65 ppm (s, 1H, aryl-H); 6.70 ppm (s, 2H, aryl-H); 7.85 ppm (m, 1H, ⁇ -NH); 7.15 ppm (d, 1H, thiophene-H); 7.50 - 7.60 ppm (dd, 2H, thiophene-H); 13.00 (s (broad), 1H, COOH).
  • ⁇ 2.40 ppm (s, 3H, CH 3 ); 5.30 ppm (d, 1 H, ⁇ -CH); 6.60-6.80 ppm (m, 4H, ⁇ -NH and aryl-H); 6.85 ppm (d, 1H, thiophene-H); 6.90 ppm (d, 1H, thiophene-H).
  • ⁇ 4.55 ppm (d, 1 H, ⁇ -CH); 6.55 ppm (s, 1H, aryl-H); 6.60 ppm (s, 2H, aryl-H); 6.75 ppm (d, 1H, thiophene H); 6.85 ppm (d, 1H, thiophene-H).
  • the investigations for determining the affinity of the compounds of the formula (I) according to the invention for the glycine binding site of the NMDA receptor channel were carried out on brain membrane homogenates (homogenate of cortex and hippocampus area from the brain of male rats, strain Wistar) ( BM Baron, BW Siegel, BL Harrison, RS Gross, C. Hawes and P. Towers, Journal of Pharmacology and Experimental Therapeutics, (1996), Vol. 279, p. 62 ).
  • cortex and hippocampus were freshly prepared from freshly drawn rat brains and dissolved in 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (10 ml / g fresh weight) with a Potter homogenizer (Braun / Melsungen; 10 strokes of the flask at 500 rpm) under ice-cooling and then centrifuged for 10 minutes at 1,000 g and 4 ° C.
  • the first supernatant was collected and the sediment resuspended with 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (5 ml / g original fresh weight) with the Potter homogenizer (10 strokes at 500 rpm) Ice cooling homogenized and centrifuged for 10 minutes at 1000 g and 4 ° C.
  • the resulting supernatant was combined with the supernatant from the first centrifugation and centrifuged at 17,000 g for 20 minutes at 4 ° C.
  • the membrane homogenate was incubated for 1 hour at 4 ° C for 30 minutes at 50,000 g and centrifuged at 4 ° C. The supernatant was discarded and the centrifuge tube sealed with the membrane sediment with parafilm and frozen at -20 ° C for 24 hours. The following day, the membrane sediment was thawed and washed with ice-cold 5 mmol / l TRIS acetate buffer, 0.1% saponin (w / v) pH 7.0 (10 ml / g original fresh weight) and homogenized with 10 strokes at 500 rpm and then for 20 minutes at 50,000 g and 4 ° C centrifuged.
  • the resulting supernatant was discarded and the sediment was taken up in a small volume with 5 mmol / l TRIS acetate buffer pH 7.0 (about 2 ml / g original fresh weight) and homogenized again with 10 strokes of the flask at 500 rpm. After determining the protein content, the membrane homogenate was adjusted to a protein concentration of 10 mg protein / ml with 5 mmol / l TRIS acetate buffer pH 7.0 and frozen in aliquots until testing.
  • the buffer used was 50 mmol / l TRIS acetate buffer pH 7.0 and the radioactive ligand 1 nmol / l ( 3 H) MDL 105,519 (Baron BM et al., 1996).
  • the proportion of non-specific binding was determined in the presence of 1 mmol / l glycine.
  • the compounds according to the invention were added in concentration series and the displacement of the radioactive ligand from its specific binding to the glycine binding site of the NMDA receptor channel was determined.
  • the respective triplicate batches were incubated for 120 minutes at 4 ° C. and then used to determine the radioactive ligands bound to the membrane homogenate were harvested by filtration through glass fiber filter mats (GF / B). The radioactivity retained on the glass fiber filters was measured after addition of scintillator in the ⁇ -counter.
  • the affinity of the compounds according to the invention for the glycine binding site of the NMDA receptor channel was calculated as IC 50 (concentration with 50% displacement of the radioactive ligand from its specific binding) according to the law of mass action by means of nonlinear regression and is shown in Table 3 after conversion (according to the Cheng Prussoff relationship) as Ki value (mean ⁇ standard deviation of 3 independent experiments) or as a percentage of the bound radioactive ligand so that is displaced from its specific binding at a concentration of 10 .mu.M of the substance according to the invention to be tested ⁇ b> Table 3 ⁇ / b> Example no.

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EP01998547A 2000-11-30 2001-11-28 Substituierte amino-furan-2-yl-essigsaure- und amino-thien-2-yl-essigsaure-derivate und ihre verwendung zur behandlung von migraine bzw. schmerz Expired - Lifetime EP1341786B9 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200130905T SI1341786T1 (sl) 2000-11-30 2001-11-28 Substituirani derivati amino-furan-2-il-ocetne kisline in amino-tien-2-il-ocetne kisline in njihova uporaba za zdravljenje migrene oz. bolečine
CY20091100279T CY1108871T1 (el) 2000-11-30 2009-03-12 Υποκατεστημενα παραγωγα αμινο-φουραν-2-υλ-οξεικου οξεος και αμινο-θειεν-2-οξεικου οξεος και η χρησιμοποιηση τους για τη θεραπεια ημικρανιας ή πονου

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Application Number Priority Date Filing Date Title
DE10059864 2000-11-30
DE10059864A DE10059864A1 (de) 2000-11-30 2000-11-30 Substituierte Amino-furan-2-yl-essigsäure- und Amino-thien-2-yl-essigsäure-Derivate
PCT/EP2001/013910 WO2002044171A1 (de) 2000-11-30 2001-11-28 Substituierte amino-furan-2-yl-essigsaure- und amino-thien-2-yl-essigsaure-derivate und ihre verwendung zur behandlung von migraine bzw. schmerz

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EP1341786A1 EP1341786A1 (de) 2003-09-10
EP1341786B1 EP1341786B1 (de) 2008-12-24
EP1341786B9 true EP1341786B9 (de) 2009-08-05

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US6794506B2 (en) * 2000-07-21 2004-09-21 Elan Pharmaceuticals, Inc. 3-(heteroaryl) alanine derivatives-inhibitors of leukocyte adhesion mediated by VLA-4
DE10125145A1 (de) * 2001-05-22 2002-11-28 Gruenenthal Gmbh Substituierte C-Furan-2-yl-methylamin- und C-Thiophen-2-yl-methylamin-Derivate
GB0302094D0 (en) 2003-01-29 2003-02-26 Pharmagene Lab Ltd EP4 receptor antagonists
DE10306203A1 (de) 2003-02-13 2004-08-26 Grünenthal GmbH Arzneimittel enthaltend substituierte 2-Heteroaryl-Aminoessigsäure-Verbindungen
DE10306202A1 (de) 2003-02-13 2004-08-26 Grünenthal GmbH Arzneimittel enthaltend substituierte 2-Aryl-Aminoessigsäure-Verbindungen und/oder substituierte 2-Heteroaryl-Aminoessigsäure-Verbindungen
GB0324269D0 (en) * 2003-10-16 2003-11-19 Pharmagene Lab Ltd EP4 receptor antagonists
WO2008009078A2 (en) 2006-07-20 2008-01-24 Gilead Sciences, Inc. 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections
US10144736B2 (en) * 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
MD3097102T2 (ro) 2015-03-04 2018-02-28 Gilead Sciences Inc Compuşi de 4,6-diamino-pirido[3,2-D]pirimidină modulatori ai receptorilor de tip Toll
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
CA3035346A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
TW202212339A (zh) 2019-04-17 2022-04-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TWI751516B (zh) 2019-04-17 2022-01-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TWI879779B (zh) 2019-06-28 2025-04-11 美商基利科學股份有限公司 類鐸受體調節劑化合物的製備方法
CN115382297B (zh) * 2022-04-12 2023-10-31 江阴市华思诚无纺布有限公司 熔体直纺双组分pet纺粘液体过滤材料及其制备方法

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JP2000514797A (ja) * 1996-06-28 2000-11-07 ユニバーシティ オブ サザン カリフォルニア 有機ホウ素誘導体を用いるアミンおよびアミノ酸の合成方法
US6441237B1 (en) 1999-02-20 2002-08-27 Boehringer Ingelheim Pharma Kg Substituted 3-phenoxy- and 3-phenylalkyloxy-2-phenyl-propylamines
DE19907385A1 (de) * 1999-02-20 2000-08-24 Boehringer Ingelheim Pharma Neue substituierte 3-Phenoxy- und 3-Phenylalkyloxy-2-phenyl-propylamine
GB0030304D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds

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NO20032340D0 (no) 2003-05-23
IL156139A0 (en) 2003-12-23
PE20020599A1 (es) 2002-08-10
ECSDI034631S (enrdf_load_html_response) 2003-07-25
DE50114605D1 (de) 2009-02-05
HUP0303041A3 (en) 2007-06-28
DE10059864A1 (de) 2002-06-13
KR20030055334A (ko) 2003-07-02
HUP0303041A2 (hu) 2003-12-29
CN1478089A (zh) 2004-02-25
US6797712B2 (en) 2004-09-28
NO20032340L (no) 2003-07-21
SK5942003A3 (en) 2003-11-04
BR0115883A (pt) 2003-12-02
NZ526554A (en) 2005-02-25
CN1326854C (zh) 2007-07-18
ZA200305009B (en) 2004-08-18
WO2002044171A1 (de) 2002-06-06
RU2003117703A (ru) 2004-12-10
PT1341786E (pt) 2009-03-31
ES2320198T3 (es) 2009-05-20
AR035658A1 (es) 2004-06-23
DK1341786T3 (da) 2009-04-20
US20040030156A1 (en) 2004-02-12
IL156139A (en) 2007-08-19
JP4340063B2 (ja) 2009-10-07
EP1341786A1 (de) 2003-09-10
CZ20031509A3 (cs) 2003-09-17
CA2430280A1 (en) 2002-06-06
CY1108871T1 (el) 2014-07-02
PL362978A1 (en) 2004-11-02
ATE418552T1 (de) 2009-01-15
SI1341786T1 (sl) 2009-04-30
AU2073502A (en) 2002-06-11
AU2002220735B2 (en) 2007-05-10
HK1059080A1 (en) 2004-06-18
EP1341786B1 (de) 2008-12-24
JP2004526675A (ja) 2004-09-02

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